PDF(Pubmed)
Abstract：
Signaling pathways of Retinoblastoma (Rb) protein, Akt-kinase, and Erk-kinase (extracellular signal-regulated kinase) have an important role in the pathogenesis of acute myeloid leukemia. Constitutive activation of these proteins by phosphorylation contributes to cell survival by regulation of cell cycle, proliferation and proapoptotic signaling processes. According to previous data phosphorylated forms of these proteins represent a worse outcome for cancer patients. We investigated the presence of phosphorylated Rb (P-Rb), Akt (P-Akt) and Erk (P-Erk) proteins by Western blot technique using phospho-specific antibodies in bone marrow or peripheral blood samples of 69 AML patients, 36 patients with myelodysplastic syndrome (MDS) and 10 healthy volunteers. Expression level of PTEN (Phosphatase and tensin homolog) and PHLPP (PH domain and leucine-rich repeat Protein Phosphatase) phosphatases, the negative regulators of Akt kinase pathway were also examined. We tested the effect of these proteins on survival and on the correlation with known prognostic features in AML. We found 46.3% of AML patients had detectable P-Rb, 34.7% had P-Akt and 28.9% had P-Erk protein. 66.1% of patients expressing PTEN, 38.9% PHLPP, 37.2% both PTEN and PHLPP and 32.2% neither PTEN nor PHLPP phosphatases. Compared to nucleophosmin mutation (NPMc) negative samples P-Erk was significantly less in nucleophosmin mutated patients, P-Rb was significantly less in patients\' group with more than 30 G/L peripheral leukocyte count by diagnosis. PHLPP was significantly present in FAB type M5. The expression of P-Rb represented significant better overall survival (OS), while P-Akt represented significantly worse event-free survival (EFS) in unfavorable cytogenetics patients. The presence of both PHLPP and PTEN phosphatases contributes to better OS and EFS, although the differences were not statistically significant. We confirmed significant positive correlation between P-Akt and PHLPP. Assessing the phosphorylation of Rb, Akt and Erk may define a subgroup of AML patients who would benefit especially from new targeted treatment options complemented the standard chemotherapy, and it may contribute to monitoring remission, relapse or progression of AML.
摘要：
视网膜母细胞瘤（Rb）蛋白的信号通路，Akt激酶,Erk激酶（细胞外信号调节激酶）在急性髓系白血病的发病机制中具有重要作用。这些蛋白质通过磷酸化的组成型激活通过调节细胞周期来促进细胞存活，增殖和促凋亡信号过程。根据先前的数据,这些蛋白质的磷酸化形式对于癌症患者代表更差的结果。我们研究了磷酸化Rb（P-Rb）的存在，Akt（P-Akt）和Erk（P-Erk）蛋白通过蛋白质印迹技术，使用69例AML患者的骨髓或外周血样本中的磷酸特异性抗体，36例骨髓增生异常综合征（MDS）患者和10例健康志愿者。PTEN（磷酸酶和张力蛋白同源物）和PHLPP（PH结构域和富含亮氨酸的重复蛋白磷酸酶）磷酸酶的表达水平，也检测了Akt激酶通路的负调节因子.我们测试了这些蛋白质对存活的影响以及与AML中已知预后特征的相关性。我们发现46.3%的AML患者有可检测的P-Rb，34.7%具有P-Akt,28.9%具有P-Erk蛋白。66.1%的患者表达PTEN,38.9%PHLPP,PTEN和PHLPP均为37.2％，PTEN和PHLPP磷酸酶均为32.2％。与核磷蛋白突变（NPMc）阴性样品相比，核磷蛋白突变患者的P-Erk明显减少，根据诊断，外周血白细胞计数超过30G/L的患者组的P-Rb明显减少。PHLPP显著存在于FAB型M5中。P-Rb的表达代表显著更好的总生存期(OS),而P-Akt代表不良细胞遗传学患者的无事件生存率（EFS）明显较差。PHLPP和PTEN磷酸酶的存在有助于更好的OS和EFS，尽管差异无统计学意义。我们证实P-Akt与PHLPP之间存在显著正相关。评估Rb的磷酸化，Akt和Erk可以定义AML患者的一个亚组，他们将受益于新的靶向治疗方案补充标准化疗。它可能有助于监测缓解，AML的复发或进展。
